Constitutive Production of NF-κB2 p52 Is Not Tumorigenic but Predisposes Mice to Inflammatory Autoimmune Disease by Repressing Bim Expression

Abstract

Normal development of the immune system requires regulated processing of NF-B2 p100 to p52, which activates NF-B2 signaling. Constitutive production of p52 has been suggested as a major mechanism underlying lymphomagenesis induced by NF-B2 mutations, which occur recurrently in a variety of human lymphoid malignancies. To test the hypothesis, we generated transgenic mice with targeted expression of p52 in lymphocytes. In contrast to their counterparts expressing the tumor-derived NF-B2 mutant p80HT, which develop predominantly B cell tumors, p52 transgenic mice are not prone to lymphomagenesis. However, they are predisposed to inflammatory autoimmune disease characterized by multiorgan infiltration of activated lymphocytes, high levels of autoantibodies in the serum, and immune complex glomerulonephritis. p52, but not p80HT, represses Bim expression, leading to defects in apoptotic processes critical for elimination of autoreactive lymphocytes and control of immune response. These findings reveal distinct signaling pathways for actions of NF-B2 mutants and p52 and suggest a causal role for sustained NF-B2 activation in the pathogenesis of autoimmunity.NF-B2 is a member of the NF-B family of transcription factors that also includes NF-B1 (p105/p50), RelA (p65), RelB, and c-Rel (1). The full-length NF-B2 protein p100 contains an N-terminal Rel homology domain, responsible for dimerization, nuclear translocation, and DNA binding. Its C-terminal region contains an ankyrin repeat domain with IB activity. Under basal conditions, NF-B2 p100 forms inhibitory complexes with Rel proteins (2-4). Phosphorylation of the C terminus of p100 by IB kinase ␣ and NF-B inducing kinase leads to proteolytic processing of p100 to p52 (5, 6). The resulting p52-Rel protein heterodimers then translocate into the nucleus and activate transcription of their target genes. This alternative NF-B signaling pathway is activated by engagement of the receptors for B cell-activating factor, lymphotoxin-␤, and CD40 ligand (3,(7)(8)(9). Previous studies with NF-B2Ϫ/Ϫ mice demonstrate a crucial role of NF-B2 in B cell development and secondary lymphoid organogenesis. These mice present a marked decrease in the peripheral B cell population and an absence of discrete perifollicular marginal and mantle zones and of germinal centers in the spleen (10, 11). More recently, it has been shown that NF-B2 signaling is essential for the development of medullary thymic epithelial cells that function as antigen-presenting cells in negative selection of autoreactive T cell clones (12).The NF-B2 gene is recurrently mutated in a variety of human lymphoid malignancies, including T-cell lymphoma, chronic lymphocytic leukemia, multiple myeloma, and B cell lymphoma (13). A cardinal feature of these genetic alterations is the generation of C-terminally truncated NF-B2 mutants that lack various portions of the ankyrin repeat domain (14 -20). To determine whether NF-B2 mutation can directly initiate lymphomagenesis, we generated transgenic mice with targeted expression in l...

Matrix Metalloproteinase-9 gene induction by a truncated oncogenic NF-κB2 protein involves the recruitment of MLL1 and MLL2 H3K4 histone methyltransferase complexes

“…Nevertheless, other data challenged the notion that p52 overproduction alone drives lymphomagenesis. Indeed, constitutive production of p52 in lymphocytes is not tumorigenic in mice but rather predisposed to an inflammatory autoimmune disease through a sustained repression of Bim, a member of the antiapoptotic Bcl-2 family (Wang et al, 2008). In contrast to Hut-78, overexpressed p52 only transiently induced TRAF1 expression in lymphocytes and rather appeared to act as homodimers harbouring repressing transcriptional activities in vitro and in vivo (Wang et al, 2008).…”

“…Indeed, constitutive production of p52 in lymphocytes is not tumorigenic in mice but rather predisposed to an inflammatory autoimmune disease through a sustained repression of Bim, a member of the antiapoptotic Bcl-2 family (Wang et al, 2008). In contrast to Hut-78, overexpressed p52 only transiently induced TRAF1 expression in lymphocytes and rather appeared to act as homodimers harbouring repressing transcriptional activities in vitro and in vivo (Wang et al, 2008). Those data are in agreement with earlier studies showing that Hut-78 harboured an enhanced transactivation potential compared to p52 (Chang et al, 1995;Epinat et al, 2000;Kim et al, 2000).…”

Mouse Models of Chronic Lymphocytic Leukemia

“…Mice with the disease contain high levels of autoantibodies in serum and immune complex glomerulonephitis (Wang et al, 2008). These results place NFB2 in the crossroad of autoimmunity and CLL and suggest that proteins controlling the transcriptional specificity of NFB2 might function as a switch for autoimmunity or CLL.…”

Integrity of IKK/NF‐κB Shields Thymic Stroma That Suppresses Susceptibility to Autoimmunity, Fungal Infection, and Carcinogenesis

“…Reduced mTEC numbers Autommunity and systemic inflammation No [38,42] TRAF6 Severely impaired mTEC development and Aire expression…”

“…Canonical and noncanonical NF-kB molecules and their regulators IKKα, IKKβ, NIK, and TRAF6 are required for mTEC development through CD40, RANK, and LTβR of the TNFR family receptors ( Table 1). [25,[31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] Notably, excepting IKKα, mice deficient in these molecules develop impaired central tolerance-associated autoimmune diseases, but they do not display manifestations with increased fungal infection and carcinogenesis.…”